Various therapeutically active quinoline carboxamides and a method for their preparation were described in International Applications No. PCT/SE99/00676, published as WO 99/55678 and No. PCT/SE99/01270, published as WO 00/03991, which applications disclosed the utility of these compounds for the treatment of diseases resulting from autoimmunity, such as multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis and, furthermore, diseases where pathologic inflammation plays a major role, such as asthma, atherosclerosis, stroke and Alzheimer's disease.
Processes for preparing therapeutically active quinoline carboxamides also have been described in International Application No. PCT/SE2003/000780, published as WO 03/106424 and in International Application No. PCT/EP2011/061490, published as WO 2012/004338. A deuterated form of a quinoline carboxamide is described in International Application No. PCT/EP2012/061798, published as WO 2012/175541.
Pharmaceutical compositions containing a salt of a quinoline carboxamide having enhanced stability during long-term storage at room temperature, methods for the manufacture of such compositions, crystalline salts of quinoline carboxamides and methods for preparing crystalline salts of quinoline carboxamides are described in the International Application No. PCT/EP2005/050485, published as WO 2005/074899.
The use of various quinoline carboxamides for the treatment of cancer, more particularly solid cancers, such as prostate cancer and breast cancer, was disclosed in International Application No. PCT/SE00/02055, published as WO 01/30758. It has been found that these compounds bind to and inhibit the interactions of an immunomodulatory protein (S100A9), which protein promotes tumor development, influences suppressive and pro-angiogenic cells in the tumor microenvironment and participates in the establishment of pre-metastatic niches.
The general term “cancer” covers a large number of malignant diseases, which may be classified in two ways: by the type of tissue in which the cancer originates (histological type) and by primary site, or the location in the body where the cancer first developed. The international standard for the classification and nomenclature of histologies is the International Classification of Diseases for Oncology, Third Edition (ICD-O-3). From a histological standpoint the cancers may be grouped into six major categories, viz. carcinoma, sarcoma, myeloma, leukemia, lymphoma and so-called mixed types.
It is now a well-established fact that angiogenesis plays an important role in the growth, progression and metastasis of solid tumors (Joyce J. A. et al., Nature Reviews Cancer 9, 239-252 (April 2009)). For example, tasquinimod, which has been shown to be a potent anti-angiogenic agent (Isaacs J. et al., Prostate 66: 1768-1778, 2006), is currently in phase III clinical development for oral treatment of castrate resistant prostate cancer (CRPC) metastatic to the bone.
Hematological malignancies are cancer types affecting blood, bone marrow, and lymph nodes. In contrast to solid tumors, hematological malignancies are generally not considered dependent on angiogenesis for disease progression.
Hematological malignancies may derive from either of the two major blood cell lineages: myeloid and lymphoid cell lines. The myeloid cell line normally produces granulocytes, erythrocytes, thrombocytes, macrophages, and mast cells, whereas the lymphoid cell line produces B, T, NK and plasma cells. Lymphomas (e.g. Hodgkin's Lymphoma), lymphocytic leukemias, and myeloma are derived from the lymphoid line, while acute and chronic myelogenous leukemia (AML, CML), myelodysplastic syndromes and myeloproliferative diseases are myeloid in origin. As blood, bone marrow, and lymph nodes are intimately connected through the immune system, a disease affecting one haematological system may affect the two others as well.
Leukemia is part of a broader group of neoplasms which affect the blood, bone marrow, and lymphoid system, known as tumors of the hematopoietic and lymphoid tissues. In leukemia the bone marrow high numbers of abnormal white blood cells are produced in the bone marrow, called blasts or leukemia cells. In 2012, leukemia developed in 352,000 people globally and caused 265,000 deaths.
The four main types of leukemia are acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML). There are also some less common forms of leukemias, not belonging to any of the aforementioned main types.
ALL is the most common type of leukemia in young children, but also affects adults, especially elderly people. Standard treatments involve chemotherapy and radiotherapy. Subtypes include precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, Burkitt's leukemia, and acute biphenotypic leukemia.
CLL most often affects adults over the age of 55, mainly men. An aggressive subtype of CLL is B-cell prolymphocytic leukemia. Hairy cell leukemia (HCL) also is sometimes considered a subtype of CLL.
AML too occurs more commonly in men than women. Except for the subtype acute promyelocytic leukemia (APL), which has a five-year survival of over 90%, the five-year survival rate in AML is as low as 40%. Subtypes of AML, other than acute promyelocytic leukemia, are acute myeloblastic leukemia, and acute megakaryoblastic leukemia.
Treatment modes for hematological malignancies often involve the use of conventional chemotherapeutic agents, such as Chlorambucil, Cyclophosphamide, Vincristine etc., generally in multi-drug treatment regimes with other types of medications, such as antimetabolite drugs or corticosteroids, or in combination with irradiation and/or bone marrow transplantation. Furthermore, tyrosine kinase inhibitors such as imatinib are being used for the treatment of leukemia, primarily CLL. However, there remains a need for further treatment options.
Roquinimex (Linomide), 4-hydroxy-N, 1-dimethyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, has been investigated for use in the treatment of various cancer diseases, including hematological malignancies.
Thus, in Bone Marrow Transplant. 2000 June; 25(11):1121-7 a study is reported where 278 AML patients received either Roquinimex 0.2 mg/kg body weight or placebo twice weekly for 2 years following autologous bone marrow transplantation (ABMT). Surviving patients were followed for up to 6.9 years. However, the study showed no benefit for Roquinimex over placebo regarding relapse or survival following ABMT for AML in remission.
In Cancer Immunol Immunother. 2002 December; 51 (11-12): 596-602, the effect of Roquinimex was investigated in BALB/c mice inoculated with B-cell leukemia (BCL1) cells and it was found that the compound had no impact on graft survival or graft versus leukemia (GVL) effects.
Thus the quinoline carboxamide Roquinimex had been tested for use in the treatment of leukemia, but had been found ineffective. In fact, in a book titled Biotic Type Antioxidants: The Prospective Search Area for Novel Chemical Drugs (VSP BV, 2000; ISBN 90-6764-308-4), the anti-angiogenic based effect of Roquinimex is mentioned as a possible explanation for the lack of activity of the compound against leukemia.
The international application WO 2012/175541 (vide supra) mentions that deuterated Tasquinimod is useful for the treatment of various malignant hyperproliferative diseases or autoimmune diseases. While leukemia is mentioned as one such disease, no data is provided for this disease. On the other hand, it is noted that the compound is capable of inhibiting prostate tumor growth via a mechanism involving an anti-angiogenic response.